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Background Early identification of individuals at risk of developing heart failure (HF) may improve poor prognosis. A dominant sympathetic activity is common in HF and associated with worse outcomes; however, less is known about the autonomic balance before HF. Hypothesis A low frequency/high frequency (L-F/H-F) ratio, index of heart rate variability, and marker of the autonomic balance predict the development of HF and may improve the performance of the HF prediction model when added to traditional cardiovascular (CV) risk factors. Methods Individuals in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study (n = 1016, all aged 70 years) were included. Exclusion criteria were prevalent HF, electrocardiographic QRS duration ≥130 millisecond, major arrhythmias, or conduction blocks at baseline. The association between the L-F/H-F ratio and incident HF was assessed using Cox proportional hazard analysis. The C-statistic evaluated whether adding the L-F/H-F-ratio to traditional CV risk factors improved the discrimination of incident HF. Results HF developed in 107/836 study participants during 15 years of follow-up. A nonlinear, inverse association between the L-F/H-F ratio and incident HF was mainly driven by an L-F/H-F ratio of <30. The association curve was flat for higher values (hazard ratio, HR for the total curve = 0.78 [95% confidence interval, CI: 0.69−0.88, p < .001]; HR = 2 for L-F/H-F ratio = 10). The traditional prediction model improved by 3.3% (p < .03) when the L-F/H-F ratio was added. Conclusions An L-F/H-F ratio of <30 was related to incident HF and improved HF prediction when added to traditional CV risk factors.

Background and Aims Patients with long atrial high-rate episodes (AHREs) >= 24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients. Methods This secondary pre-specified analysis of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes (NOAH-AFNET 6) trial examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared with placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and electrocardiogram (ECG)-diagnosed atrial fibrillation. Results Median follow-up of 2389 patients with core lab-verified AHRE was 1.8 years. AHRE >= 24 h were present at baseline in 259/2389 patients (11%, 78 +/- 7 years old, 28% women, CHA2DS2-VASc 4). Clinical characteristics were not different from patients with shorter AHRE. The primary outcome occurred in 9/132 patients with AHRE >= 24 h (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). Atrial high-rate episode duration did not interact with the efficacy (P-interaction = .65) or safety (P-interaction = .98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE >= 24 h developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; P < .001). Conclusions This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent “non-ischemic” myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the “Padua criteria” were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late‑gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other “non-scarring” myocardial disease. The “ring-like’ pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framewor

Aims: Atrial fibrillation (AF) recurrence during the first year after catheter ablation remains common. Patient-specific prediction of arrhythmic recurrence would improve patient selection, and, potentially, avoid futile interventions. Available prediction algorithms, however, achieve unsatisfactory performance. Aim of the present study was to derive from ESC-EHRA Atrial Fibrillation Ablation Long-Term Registry (AFA-LT) a machine-learning scoring system based on pre-procedural, easily accessible clinical variables to predict the probability of 1-year arrhythmic recurrence after catheter ablation. Methods and results: Patients were randomly split into a training (80%) and a testing cohort (20%). Four different supervised machine-learning models (decision tree, random forest, AdaBoost, and k-nearest neighbour) were developed on the training cohort and hyperparameters were tuned using 10-fold cross validation. The model with the best discriminative performance on the testing cohort (area under the curve-AUC) was selected and underwent further optimization, including re-calibration. A total of 3128 patients were included. The random forest model showed the best performance on the testing cohort; a 19-variable version achieved good discriminative performance [AUC 0.721, 95% confidence interval (CI) 0.680-0.764], outperforming existing scores (e.g. APPLE score: AUC 0.557, 95% CI 0.506-0.607). Platt scaling was used to calibrate the model. The final calibrated model was implemented in a web calculator, freely available at http://afarec.hpc4ai.unito.ti/. Conclusion: AFA-Recur, a machine-learning-based probability score predicting 1-year risk of recurrent atrial arrhythmia after AF ablation, achieved good predictive performance, significantly better than currently available tools. The calculator, freely available online, allows patient-specific predictions, favouring tailored therapeutic approaches for the individual patient.

Aims To allow timely initiation of anticoagulation therapy for the prevention of stroke, the European guidelines on atrial fibrillation (AF) recommend remote monitoring (RM) of device-detected atrial high-rate episodes (AHREs) and progression of arrhythmia duration along pre-specified strata (6 min...<1h, 1 h...<24 h, >= 24h). We used the MATRIX registry data to assess the capability of a single-lead implantable cardioverter-defibrillator (ICD) with atrial sensing dipole (DX ICD system) to follow this recommendation in patients with standard indication for single-chamber ICD. Methods and results In 1841 DX ICD patients with daily automatic RM transmissions, electrograms of first device-detected AHREs per patient in each duration stratum were adjudicated, and the corresponding positive predictive values (PPVs) for the detections to be true atrial arrhythmia were calculated. Moreover, the incidence and progression of new-onset AF was assessed in 1451 patients with no AF history. A total of 610 AHREs >= 6min were adjudicated. The PPV was 95.1% (271 of 285) for episodes 6min...<1h, 99.6% (253/254) for episodes 1 h...<24h, 100% (71/71) for episodes >= 24h, or 97.5% for all episodes (595/610). The incidence of new-onset AF was 8.2% (119/1451), and in 31.1% of them (37/119), new-onset AF progressed to a higher duration stratum. Nearly 80% of new-onset AF patients had high CHA(2)DS(2)-VASc stroke risk, and 70% were not on anticoagulation therapy. Age was the only significant predictor of new-onset AF. Conclusion A 99.7% detection accuracy for AHRE >= 1h in patients with DX ICD systems in combination with daily RM allows a reliable guideline-recommended screening for subclinical AF and monitoring of AF-duration progression. [Graphics] .

BackgroundThere are limited comparative data on safety and efficacy within commonly used Vaughan-Williams (VW) class III antiarrhythmic drugs (AADs) for maintenance of sinus rhythm in adults with atrial fibrillation (AF). HypothesisWe hypothesized that dronedarone and sotalol, two commonly prescribed VW class III AADs with class II properties, have different safety and efficacy effects in patients with nonpermanent AF. MethodsA systematic literature review was conducted searching MEDLINE (R), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to June 15, 2021 (NCT05279833). Clinical trials and observational studies that evaluated safety and efficacy of dronedarone or sotalol in adults with AF were included. Bayesian random-effects network meta-analysis (NMA) was used to quantify comparative safety and efficacy. Where feasible, we performed sensitivity analyses by including only randomized controlled trials (RCTs). ResultsOf 3581 records identified through database searches, 37 unique studies (23 RCTs, 13 observational studies, and 1 nonrandomized trial) were included in the NMA. Dronedarone was associated with a statistically significantly lower risk of all-cause death versus sotalol (hazard ratio [HR] = 0.38 [95% credible interval, CrI: 0.19, 0.74]). The association was numerically similar in the sensitivity analysis (HR = 0.46 [95% CrI: 0.21, 1.02]). AF recurrence and cardiovascular death results were not significantly different between dronedarone and sotalol in all-studies and sensitivity analyses. ConclusionThe NMA findings indicate that, across all clinical trials and observational studies included, dronedarone compared with sotalol was associated with a lower risk of all-cause death, but with no difference in AF recurrence.

Aims: This post hoc analysis of the ATHENA trial (NCT00174785) assessed the effect of dronedarone on the estimated burden of atrial fibrillation (AF)/atrial flutter (AFL) progression to presumed permanent AF/AFL, and regression to sinus rhythm (SR), compared with placebo. Methods and results: The burden of AF/AFL was estimated by a modified Rosendaal method using available electrocardiograms (ECG). Cumulative incidence of permanent AF/AFL (defined as >= 6 months of AF/AFL until end of study) or permanent SR (defined as >= 6 months of SR until end of study) were calculated using Kaplan-Meier estimates. A log-rank test was used to assess statistical significance. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated using a Cox model, adjusted for treatment group. Of the 4439 patients included in this analysis, 2208 received dronedarone, and 2231 placebo. Baseline and clinical characteristics were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to permanent AF/AFL compared with 455 (20.4%) treated with placebo (P < 0.0001). Compared with those receiving placebo, patients receiving dronedarone had a lower cumulative incidence of permanent AF/AFL (log-rank P < 0.001; HR: 0.65; 95% CI: 0.56-0.75), a higher cumulative incidence of permanent SR (log-rank P < 0.001; HR: 1.19; 95% CI: 1.09-1.29), and a lower estimated AF/AFL burden over time (P < 0.01 from Day 14 to Month 21). Conclusion: These results suggest that dronedarone could be a useful antiarrhythmic drug for early rhythm control due to less AF/AFL progression and more regression to SR vs. placebo, potentially reflecting reverse remodeling.

Background: The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) in early stages is challenging. The aim was therefore to study whether electrocardiographic imaging (ECGI) can detect epicardial depolarization changes in ARVC patients and healthy mutation-carriers (M-carriers). Method: Twelve ARVC patients, 20 M-carriers and 8 controls underwent 12-lead ECG, signal-averaged ECG, 2-dimensional echocardiography, 24-hours Holter monitoring and ECGI (body surface mapping and computer tomography with offline analysis of reconstructed epicardial signals). Total and Right Ventricular Activation Time (tVAT and RVAT respectively), area of Ventricular Activation during the terminal 20 milliseconds (aVAte20) and the activation patterns were compared between groups. Results: In ARVC patients the locations of aVAte20 were scattered or limited to smaller RV parts versus in controls, in whom aVAte20 was confined to RVOT and LV base (+/- RV base). ARVC patients had smaller aVAte20 (35cm2 vs 87cm2, p<0.05), longer tVAT (99msec vs 58msec, p<0.05) and longer RVAT (66msec vs 43msec, p<0.05) versus controls. In 50% of M-carriers, the locations of aVAte20 were also eccentric. This sub-group presented smaller aVAte20 (53cm2 vs 87cm2, p= 0.009), longer RVAT (55msec vs 48msec, p=0.043), but similar tVAT (65msec vs 60msec, p=0.529) compared with the M-carriers with normal activation pattern. Conclusions: The observation of localized delayed epicardial conduction in the RV in M-carriers suggests an early stage of ARVC and may be a useful diagnostic marker enhancing an early detection of the disease.

Infection remains a serious complication associated with the cardiac implantable electronic devices (CIEDs), leading to substantial clinical and economic burden globally. This review assesses the burden of cardiac implantable electronic device infection (CIED-I), evidence for treatment recommendations, barriers to early diagnosis and appropriate therapy, and potential solutions. Multiple clinical practice guidelines recommended complete system and lead removal for CIED-I when appropriate. CIED extraction for infection has been consistently reported with high success, low complication, and very low mortality rates. Complete and early extraction was associated with significantly better clinical and economic outcome compared with no or late extraction. However, significant gaps in knowledge and poor recommendation compliance have been reported. Barriers to optimal management may include diagnostic delay, knowledge gaps, and limited access to expertise. A multipronged approach, including education of all stakeholders, a CIED-I alert system, and improving access to experts, could help bring paradigm shift in the treatment of this serious condition. (J Am Coll Cardiol 2023;81:1283-1295)

Aims: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as 'pill-in-the-pocket' (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated. Methods and results: The recently published Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) survey included questions regarding current PITP usage, stratified by US vs. European countries surveyed, by representative countries within Europe, and by cardiologists vs. electrophysiologists. This manuscript presents the data from this planned sub-study. Our survey revealed that clinicians in both the USA and Europe consider PITP in about a quarter of their patients, mostly for recent-onset AF with minimal or no structural heart disease (guideline appropriate). However, significant deviations exist. See the Graphical abstract for a summary of the data. Conclusion: Our findings highlight the frequent use of PITP and the need for further physician education about appropriate and optimal use of this strategy.

Background: For conditions with rare clinical outcomes, real-world treatment comparisons are challenging to design and prone to confounding. Objectives: To present a robust methodologic approach for rigorous and transparent assessment of rare outcomes using real-world data. Methods: We emulated a target trial using an active comparator, new-user design to compare dronedarone to sotalol for rhythm control in atrial fibrillation (AF) as both are recommended for similar patient phenotypes. Using one protocol, a pre-specified stepwise approach was implemented across 4 datasets (Optum CDM; IBM MarketScan; Veterans Affairs Electronic Health Records; Swedish National Patient Register). Meta-analysis was used to ensure sufficient capture of specific, rare primary outcomes (cardiovascular (CV) hospitalization and ventricular proarrhythmia) and to evaluate consistency of findings across patient populations. Steps 1–3 focused on cohort selection, propensity score matching (PSM), baseline equipoise and residual confounding assessment via negative control outcome analyses. In steps 4–6, outcomes in the individual cohorts were analyzed using an as-treated approach and Cox proportional hazards models. Step 7 included a heterogeneity assessment, meta-analysis using fixed effects models, and hypothesis testing using a hierarchical approach. In step 8, sensitivity analyses, including E-values and Inverse Probability of Censoring Weighting, were conducted to verify the robustness of findings. Results: In step 1, 35,467 sotalol and 27,955 dronedarone patients with AF who were antiarrhythmic drug-naive were identified across databases. In steps 2–3, 23,275 dronedarone patients were PS-matched to 23,275 sotalol patients. Baseline covariates were well-balanced and little-to-no residual confounding was observed via the negative control analyses. Individual HRs were estimated in steps 4–6, and, when no significant heterogeneity between databases was observed, hazard ratios (HRs) were pooled

The risk of stroke in patients with atrial high-rate episodes (AHREs) depends on age, comorbidities and AHRE burden. Two randomized clinical trials on the use of oral anticoagulant therapy for stroke prevention in older patients with short and rare AHREs have reported conflicting findings on the efficacy of oral anticoagulation in this patient population, although both trials report a significantly increased risk of major bleeding with oral anticoagulation.

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as 'pill-in-the-pocket' (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated. METHODS AND RESULTS: The recently published Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) survey included questions regarding current PITP usage, stratified by US vs. European countries surveyed, by representative countries within Europe, and by cardiologists vs. electrophysiologists. This manuscript presents the data from this planned sub-study. Our survey revealed that clinicians in both the USA and Europe consider PITP in about a quarter of their patients, mostly for recent-onset AF with minimal or no structural heart disease (guideline appropriate). However, significant deviations exist. See the Graphical abstract for a summary of the data. CONCLUSION: Our findings highlight the frequent use of PITP and the need for further physician education about appropriate and optimal use of this strategy.